Role of Immune System in Lupus Emerging from Genomics

Action Points

Explain to interested patients that lupus is regarded as an autoimmune disease, but exactly how the disease develops remains unclear.

Note that these studies suggest that many parts of the immune system have a role in the pathogenesis of lupus.

NEW YORK, Jan. 21 -- Many aspects of the immune system appear to play a role in the pathophysiology of systemic lupus erythematosus, according to researchers here and in several other centers worldwide.

Two large genomic studies and two smaller analyses published this week implicate the innate immune system, T- and B-cell function, cytokine production, and a host of other immune functions.

"These studies give us confidence that we're on the right track in looking at these various aspects of the immune system," said Mary Crow, M.D., of the Hospital for Special Surgery here.

Dr. Crow was not involved in the four studies, but commented on them in an online editorial in the Jan. 20 issue of the New England Journal of Medicine, where one of the large genomic studies was also published. The remaining three studies appeared in the Jan. 20 issue of Nature Genetics.

Overall, the studies confirm several previously identified genetic associations with lupus, including links to the HLA complex, but also identify several new genetic regions associated with the disease.

Researchers in the International Consortium for Systemic Lupus Erythematosus Genetics (SLEGEN), led by Carl Langefeld, Ph.D., of Wake Forest University, identified four novel regions significantly linked to lupus.

The researchers used genome-wide scanning techniques in a case-control study involving 2,566 cases (in an initial cohort and a replication cohort) and 4,162 controls.

Dr. Langefeld and colleagues linked lupus to:

A single nucleotide polymorphism (SNP) dubbed rs10798269 on chromosome one. The association was significant at P=1.11x10-7.

A gene called PXK on chromosome three. The association was significant at P=9.2x10-7.

A gene called KIAA1542 on chromosome 11. The association was significant at P=1.3x10-7.

And a gene called ITGAM on chromosome 16. The association was significant at P=1.9x10-8.

The researchers also reported in Nature Genetics several other regions that are possibly -- but less clearly -- linked to the disease.

A second team, also using genome-wide scanning techniques, also found a link to ITGAM, which encodes an adhesion molecule, variously called MAC-1, CD11b, and complement receptor type 3, that plays a role in the interaction between white blood cells and endothelial cells.

Researchers led by Timothy Behrens, M.D., of Genentech, in South San Francisco, reported in the NEJM that ITGAM was significantly associated with the risk of lupus, at P=3x10-11.

The finding also came from a large case-control study, with a total of 2,104 cases (also in two cohorts) and 4,197 controls.

The researchers also pinpointed another region involving two genes on chromosome eight, BLK and C8orf13, that was significantly associated (P=1x10-10) with lupus.

The function of C8orf13 isn't known, but BLK expression is largely restricted to B cells. Although the role of BLK hasn't been studied, the researchers speculated that altered levels of its protein might predispose people to lupus.

"These findings underscore that numerous genes, which are often immune-function related, contribute to the risk of developing lupus," Dr. Langefeld said.

A third study -- some of whose authors overlapped those in the SLEGEN study -- delved more deeply into the ITGAM association and found a 78% increase in risk for people who carry a single nucleotide polymorphism, rs1143679, in the gene.

The increased risk (significant at P=1.7x10-17) was found by studying the genomes of 3,818 individuals of European descent and replicated in two groups of those of African descent, where the association remained significant.

The study, led by Swapan Nath, Ph.D., of the Oklahoma Medical Research Foundation in Oklahoma City, was the only one of the four to involve patients of non-European descent.

That's a significant limitation, Dr. Crow said, because the disease often is particularly severe in African Americans, Asians, and some Hispanic populations.

"There may be additional genes that don't even come up in these studies" because their target populations are largely European, she said.

Dr. Crow noted, however, that the link with ITGAM harkens back to the early days of lupus studies, when researchers focused on the vascular pathology of the disease.

The ITGAM link described by Dr. Nath and colleagues "raises the possibility that interactions between white blood cells and the vascular endothelium might be different in individuals with this variation."

The final study, led by Marta AlarcÃ³n-Riquelme, M.D., Ph.D., of Uppsala University in Sweden, found that another gene involved in B-cell function, BANK1, is linked to lupus.

The researchers studied SNPs in 279 Swedish patients and 515 controls, and found one -- rs10516487 -- in BANK1 that was significantly associated with the disease.

They replicated the finding in four independent sets of cases and controls with a total of 1,757 cases and 1,540 controls. The combined significance of the association was P=3.7x10-10.

Dr. AlarcÃ³n-Riquelme and colleagues noted that the role of the gene in B-cell signaling is not clear and suggested that further experiments will be needed to understand "if, and how, BANK1 polymorphisms" lead to lupus.

While the studies were published separately, there was considerable overlap among the authors, with some appearing on three of the four papers.

The SLEGEN study was supported by the Alliance for Lupus Research, the NIH, the Mary Kirkland Awards, the Department of Veterans Affairs, the Lupus Foundation of Minnesota, the Knut and Alice Wallenberg Foundation, the Torsten & Ragnar SÃ¶derbergs Foundation, the Swedish Research Council, and a Wellcome Trust Senior Fellowship. The researchers reported competing financial interests.

The New England Journal study was supported by the NIH, a Kirkland Scholar Award, the Rosalind Russell Medical Research Center for Arthritis, the National Center for Research Resources, the Swedish Research Council for Medicine, the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Association, the King Gustaf V 80-Year Foundation, and the Ulla and Roland Gustafsson Foundation. Several of the authors, including Dr. Behrens, are employees of Genentech or and have equity in the company.

The study led by Dr. Nath was supported by the NIH, the Alliance for Lupus Research, a Mary Kirkland Scholarship, and the Department of Veterans Affairs. The researchers did not report competing financial interests.

The study led by Dr. AlarcÃ³n-Riquelme was supported by the European Commission, the Swedish Research Council for Medicine, the Swedish Association against Rheumatism, the Magnus Bergwalls Foundation, the Gustaf V: 80th-year Jubilee Foundation, the Torsten and Ragnar SÃ¶derbergs Foundation, the Marcus BorsgtrÃ¶ms Foundation, the Gurli and Edward Brunnbergs Foundation for rheumatologic research, the Knut and Alice Wallenberg Foundation, by FISM, Regione Piemonte the Bundesministerium fÃ¼r Bildung und Forschung Kompetenznetz Rheuma C2.12, Germany, and the Danish Rheumatism Association. The researchers reported competing financial interests.

Dr. Crow reported an equity interest in XDx, being an inventor on an application for a patent on an assay for type I interferon, and serving on an advisory board for the Alliance for Lupus Research.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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